Publications by authors named "Marco De Martino"

33 Publications

Critical role of the high mobility group A proteins in hematological malignancies.

Hematol Oncol 2021 Oct 12. Epub 2021 Oct 12.

Department of Molecular Medicine and Medical Biotechnology (DMMBM), National Research Council (CNR), Institute for Experimental Endocrinology and Oncology (IEOS) "G. Salvatore", University of Naples "Federico II", Naples, Italy.

The high mobility group A (HMGA) protein family is composed of three non-histone chromatin remodeling proteins that act as architectural transcriptional factors. Indeed, although HMGA proteins lack transcriptional activity per se, they bind the minor groove of DNA at AT-rich sequences, and, interacting with the transcription machinery, are able to modify chromatin modeling, thus regulating the expression of several genes. HMGA proteins have been deeply involved in embryogenesis process, and a large volume of studies has pointed out their key role in human cancer. Here, we review the studies on the role of the HMGA proteins in human hematological malignancies: they are overexpressed in most of the cases and their expression correlates with a reduced survival. In some cases, such as in acute lymphoblastic leukemia and acute myelogenous leukemia, HMGA2 gene rearrangements have been also described. Finally, recent studies evidence a synergism between HMGA and EZH2 in diffuse B-cell lymphomas, suggesting an innovative therapy for this disease based on the inhibition of the function of both these proteins.
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http://dx.doi.org/10.1002/hon.2934DOI Listing
October 2021

Publisher Correction: HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2021 Jun 11;11(1):12741. Epub 2021 Jun 11.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

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http://dx.doi.org/10.1038/s41598-021-92173-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196011PMC
June 2021

HMGA1 induces EZH2 overexpression in human B-cell lymphomas.

Am J Cancer Res 2021 15;11(5):2174-2187. Epub 2021 May 15.

Institute of Endocrinology and Experimental Oncology-CNR c/o Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II" Naples, Italy.

EZH2 is an enzymatic subunit of PRC2, an epigenetic regulator that triggers the methylation of the histone H3 lysine 27 silencing the transcription of several genes. EZH2 has a critical role in cancer progression, since its overexpression has been associated with increased cancer cell invasiveness, drug resistance and poor patient survival. However, the mechanisms accounting for EZH2 overexpression in cancer remain still unclear. Intriguingly, also HMGA protein overexpression is a feature of many human malignancies and correlates with the presence of metastases and a poor outcome. The HMGA proteins, including HMGA1 and HMGA2, belong to the architectural transcription factors that play a key role in the organization of chromatin structure. Here, we report a statistically significant correlation between HMGA1 and EZH2 expression in human lymphomas. We demonstrate that HMGA1 is able to bind promoter and induce its activity. Consistently, silencing of expression results in the downregulation of the levels leading to a decreased proliferation and migration rate of human lymphoma cell lines. Therefore, these data identify HMGA1 as an activator, suggesting a novel molecular mechanism contributing to EZH2 overexpression in human malignancies and a synergism of these proteins in cancer progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167683PMC
May 2021

MPPED2 is downregulated in glioblastoma, and its restoration inhibits proliferation and increases the sensitivity to temozolomide of glioblastoma cells.

Cell Cycle 2021 04 18;20(7):716-729. Epub 2021 Mar 18.

Institute for Experimental Endocrinology and Oncology (IEOS) "G. Salvatore", National Research Council (CNR), Naples, Italy.

Glioblastoma (GBM) is the most aggressive and lethal neoplasia of the central nervous system in adults. Based on the molecular signature genes, GBM has been classified in proneural, neural, mesenchymal and classical subtypes. The Metallophosphoesterase-domain-containing protein 2 () gene encodes a metallophosphodiesterase protein highly conserved throughout the evolution. MPPED2 downregulation, likely due to its promoter hypermethylation, has been found in several malignant neoplasias and correlated with a poor prognosis. In this study, we aimed to investigate the expression and the functional role of MPPED2 in GBM. TCGA and Gravendeel databases were employed to explore the expression levels in this type of tumor. We have found that expression is downregulated in GBM patients, showing a positive correlation with survival. Moreover, TCGA and Gravendeel data also revealed that expression negatively correlates with the most aggressive mesenchymal subtype. Additionally, the restoration of expression in U251 and GLI36 GBM cell lines decreases cell growth, migration and enhanced the sensitivity to the temozolomide, inducing apoptotic cell death, of GBM cells. These findings suggest that the restoration of MPPED2 function can be taken into consideration for an innovative GBM therapy.
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http://dx.doi.org/10.1080/15384101.2021.1901042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078659PMC
April 2021

miRNAs and Biomarkers in Testicular Germ Cell Tumors: An Update.

Int J Mol Sci 2021 Jan 30;22(3). Epub 2021 Jan 30.

Istituto di Endocrinologia ed Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Napoli 80131, Italy.

Testicular germ cell tumors (TGCTs) are the leading form of solid cancer and death affecting males between the ages of 20 and 40. Today, their surgical resection and chemotherapy are the treatments of first choice, even if sometimes this is not enough to save the lives of patients with TGCT. As seen for several tumors, the deregulation of microRNAs (miRNAs) is also a key feature in TGCTs. miRNAs are small molecules of RNA with biological activity that are released into biological fluids by testicular cancer cells. Their presence, therefore, can be detected and monitored by considering miRNAs as diagnostic and prognostic markers for TGCTs. The purpose of this review is to collect all the studies executed on miRNAs that have a potential role as biomarkers for testicular tumors.
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http://dx.doi.org/10.3390/ijms22031380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866514PMC
January 2021

The shows oncogenic activity .

Cell Cycle 2020 11 10;19(22):2955-2959. Epub 2020 Oct 10.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli "Federico II" , Naples, Italy.

We have recently reported that transgenic mice overexpressing the develop hematological neoplasia marked by monoclonal B-cell populations, and diagnosed as Diffuse Large B-cell Lymphoma. These findings prove the oncogenic role .
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http://dx.doi.org/10.1080/15384101.2020.1829825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714516PMC
November 2020

Interplay between HMGA and TP53 in cell cycle control along tumor progression.

Cell Mol Life Sci 2021 Feb 12;78(3):817-831. Epub 2020 Sep 12.

Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Prédio de Ciências da Saúde-Cidade Universitária, Ilha do Fundão, A. Carlos Chagas, 373-Bloco F, Sala 26, 21941-902, Rio de Janeiro, RJ, Brazil.

The high mobility group A (HMGA) proteins are found to be aberrantly expressed in several tumors. Studies (in vitro and in vivo) have shown that HMGA protein overexpression has a causative role in carcinogenesis process. HMGA proteins regulate cell cycle progression through distinct mechanisms which strongly influence its normal dynamics along malignant transformation. Tumor protein p53 (TP53) is the most frequently altered gene in cancer. The loss of its activity is recognized as the fall of a barrier that enables neoplastic transformation. Among the different functions, TP53 signaling pathway is tightly involved in control of cell cycle, with cell cycle arrest being the main biological outcome observed upon p53 activation, which prevents accumulation of damaged DNA, as well as genomic instability. Therefore, the interaction and opposing effects of HMGA and p53 proteins on regulation of cell cycle in normal and tumor cells are discussed in this review. HMGA proteins and p53 may reciprocally regulate the expression and/or activity of each other, leading to the counteraction of their regulation mechanisms at different stages of the cell cycle. The existence of a functional crosstalk between these proteins in the control of cell cycle could open the possibility of targeting HMGA and p53 in combination with other therapeutic strategies, particularly those that target cell cycle regulation, to improve the management and prognosis of cancer patients.
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http://dx.doi.org/10.1007/s00018-020-03634-4DOI Listing
February 2021

An update on microRNAs as potential novel therapeutic targets in testicular germ cell tumors.

Intractable Rare Dis Res 2020 Aug;9(3):184-186

Dipartimento di Psicologia, Università della Campania "Luigi Vanvitelli", Caserta, Italy.

Testicular germ cell tumors (TGCTs) are the most frequent solid malignant tumors in men 20- 40 years of age and the most frequent cause of death from solid tumors in this age group. Recent studies have underscored the fact that miRNA deregulation is a feature of carcinogenesis, including TGCT development and progression. MiRNAs are a group of small noncoding RNAs that bind to the 3'-untranslated region (UTR) of the targeted mRNAs, thus causing mRNA degradation or the inhibition of its translation, regulating gene expression in a temporal and tissue-specific manner. However, few miRNAs have been found to play key roles in TGCTs; recently, other miRNAs have been identified, representing novel potential therapeutic targets.
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http://dx.doi.org/10.5582/irdr.2020.03025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441029PMC
August 2020

Characterization of transgenic mouse embryonic fibroblasts.

Cell Cycle 2020 09 13;19(18):2281-2285. Epub 2020 Aug 13.

Istituto di Endocrinologia Ed Oncologia Sperimentale del CNR C/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi Di Napoli "Federico II" , Naples, Italy.

Latest studies have shown that deregulated pseudogene transcripts contribute to cancer working as competing endogenous RNAs. Our research group has recently demonstrated that the overexpression of two pseudogenes, and , has a critical role in cancer progression. These pseudogenes work sustaining the expression of HMGA1 and other cancer-related genes. We generated a mouse model overexpressing to better study the -pseudogene function in a more physiological context. Here, we show the proliferation rate and the susceptibility to senescence of mouse embryonic fibroblasts obtained from -overexpressing mice to better characterize the HMGA1-pseudogene function. Indeed, our study reports that mouse embryonic fibroblasts (MEFs) derived from mice express higher HMGA1 mRNA and protein levels. Moreover, these cells grow faster and senesce later than wild-type sustaining the oncogenic role of ceRNA crosstalk mediated by .
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http://dx.doi.org/10.1080/15384101.2020.1807080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513866PMC
September 2020

HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

Department of Psychology, University of Campania "L. Vanvitelli", 81100 Caserta, Italy.

Background: Recent studies have underlined HMGA protein's key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a-two -targeting microRNAs.

Methods: mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities.

Results: an inverse correlation was found between the expression of miR-26a and Let-7a and expression levels in seminomas samples, suggesting a critical role of these microRNAs in levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2.

Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is-at least in part-due to the downregulation of -targeting microRNAs.
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http://dx.doi.org/10.3390/ijms21083014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215726PMC
April 2020

HMGA1-pseudogene7 transgenic mice develop B cell lymphomas.

Sci Rep 2020 04 27;10(1):7057. Epub 2020 Apr 27.

Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

We have recently identified and characterized two pseudogenes (HMGA1P6 and HMGA1P7) of the HMGA1 gene, which has a critical role in malignant cell transformation and cancer progression. HMGA1P6 and HMGAP17 act as microRNA decoy for HMGA1 and other cancer-related genes upregulating their protein levels. We have previously shown that they are upregulated in several human carcinomas, and their expression positively correlates with a poor prognosis and an advanced cancer stage. To evaluate in vivo oncogenic activity of HMGA1 pseudogenes, we have generated a HMGA1P7 transgenic mouse line overexpressing this pseudogene. By a mean age of 12 months, about 50% of the transgenic mice developed splenomegaly and accumulation of lymphoid cells in several body compartments. For these mice FACS and immunohistochemical analyses suggested the diagnosis of B-cell lymphoma that was further supported by clonality analyses and RNA expression profile of the pathological tissues of the HMGA1P7 transgenic tissues. Therefore, these results clearly demonstrate the oncogenic activity of HMGA1 pseudogenes in vivo.
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http://dx.doi.org/10.1038/s41598-020-62974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184748PMC
April 2020

Is Peripheral Artery Disease an Independent Predictor of Isolated Coronary Artery Bypass Outcome?

Heart Lung Circ 2020 Oct 25;29(10):1502-1510. Epub 2020 Feb 25.

Cardiac Surgery Unit, Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy; Cardiovascular Research Institute Maastricht - CARIM, Maastricht University Medical Centre, The Netherlands.

Aim: The aim was to use a propensity score-based analysis to determine the impact of peripheral artery disease (PAD) on early outcomes after coronary artery bypass surgery grafting (CABG) in patients with PAD.

Method: We conducted a multicentre retrospective analysis of 11,311 consecutive patients who underwent CABG between 1997 and 2017. Patients with previous or concomitant vascular surgery were excluded. The main endpoints were death, stroke, and limb ischaemia requiring percutaneous or surgical revascularisation. Subgroup analyses were performed to test the interaction of PAD with concomitant factors.

Results: There was no difference in mortality in patients with and without PAD (p=0.06 and p=0.179, respectively). Patients with PAD had a greater incidence of stroke (p=0.04), acute kidney disease (p=0.003), and limb ischaemia requiring interventions (p<0.001) than those without PAD. The use of off-pump or no-touch aortic techniques did not influence the effect of PAD on the outcomes. Early mortality rate increased in patients with PAD when associated with long cardiopulmonary bypass, cross-clamp times (both p<0.001), and postoperative low cardiac output (p=0.01).

Conclusions: The presence of PAD is associated, independently of other factors, with greater incidence of stroke, acute kidney disease, and limb ischaemia following CABG, irrespective of the technique employed. Operative mortality was greater in patients with PAD only when associated with long cardiopulmonary bypass and aortic cross-clamp times, and low cardiac output.
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http://dx.doi.org/10.1016/j.hlc.2020.01.013DOI Listing
October 2020

Further insights into testicular germ cell tumor oncogenesis: potential therapeutic targets.

Expert Rev Anticancer Ther 2020 03 12;20(3):189-195. Epub 2020 Mar 12.

Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli 'Federico II', Naples, Italy.

: Testicular germ cell tumors (TGCTs) are the most common neoplasia in the young male population, and the incidence has been constantly increasing in many parts of the world. These tumors are classified into seminomas and non-seminomas, and those divided, in turn, into yolk sac tumors, embryonal cell carcinomas, choriocarcinomas, and teratomas. Although therapeutic approaches have improved, approximately 25% of the patients relapse or, in a small number of cases, show platinum-resistant disease.: We review several molecular targets that have recently emerged as powerful tools for both diagnosis and therapy of TGCTs. Moreover, we reviewed the most frequent deregulated pathways involved in TGCT tumorigenesis, reporting drugs that may emerge as novel therapeutic agents.: TGCT treatment is mainly based on platinum-derivative therapy with high cure rates. However, in the refractory patients, there are few alternative treatments. Thus, different pharmacological approaches have to be thoroughly investigated to shed new light on TGCT pathogenesis and treatment.
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http://dx.doi.org/10.1080/14737140.2020.1736566DOI Listing
March 2020

HMGA and Cancer: A Review on Patent Literatures.

Recent Pat Anticancer Drug Discov 2019 ;14(3):258-267

Istituto di Endocrinologia e Oncologia Sperimentale-CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli "Federico II", via Pansini 5, Naples 80131, Italy.

Background: The high mobility group A proteins modulate the transcription of numerous genes by interacting with transcription factors and/or altering the structure of chromatin. These proteins are involved in both benign and malignant neoplasias as a result of several pathways. A large amount of benign human mesenchymal tumors has rearrangements of HMGA genes. On the contrary, malignant tumors show unarranged HMGA overexpression that is frequently and causally related to neoplastic cell transformation. Here, we review the function of the HMGA proteins in human neoplastic disorders, the pathways by which they contribute to carcinogenesis and the new patents focused on targeting HMGA proteins.

Objective: Current review was conducted to check the involvement of HMGA as a druggable target in cancer treatment.

Methods: We reviewed the most recent patents focused on targeting HMGA in cancer treatment analyzing patent literature published during the last years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents.

Results: HMGA proteins are intriguing targets for cancer therapy and are objects of different patents based on the use of DNA aptamers, inhibitors, oncolytic viruses, antisense molecules able to block their oncogenic functions.

Conclusion: Powerful strategies able to selectively interfere with HMGA expression and function could represent a helpful approach in the development of new anti-cancer therapies.
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http://dx.doi.org/10.2174/1574892814666190919152001DOI Listing
May 2020

Emerging Role of USP8, HMGA, and Non-Coding RNAs in Pituitary Tumorigenesis.

Cancers (Basel) 2019 Sep 4;11(9). Epub 2019 Sep 4.

Istituto di Endocrinologia ed Oncologia Sperimentale-Consiglio Nazionale delle Ricerche (CNR) c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", 80131 Naples, Italy.

Two novel molecular mechanisms with a driver role in pituitary tumorigenesis have been recently identified. They are (a) mutations in the Ubiquitin-Specific Protease 8 (USP8) gene in corticotroph tumors and (b) overexpression of the and genes in most of the pituitary tumors. Moreover, deregulated expression of the non-coding RNAs has been very frequently observed in this neoplasia. The aim of this review is to better elucidate the role, the mechanisms, and the possible clinical impact of these novel alterations in the development of pituitary neoplasia.
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http://dx.doi.org/10.3390/cancers11091302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770943PMC
September 2019

HMGA1 negatively regulates NUMB expression at transcriptional and post transcriptional level in glioblastoma stem cells.

Cell Cycle 2019 07 22;18(13):1446-1457. Epub 2019 May 22.

a Istituto di Endocrinologia ed Oncologia Sperimentale - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche , Università degli Studi di Napoli "Federico II" , Naples , Italy.

Glioblastoma (GBM) is a lethal, fast-growing brain cancer, affecting 2-3 per 100,000 adults per year. It arises from multipotent neural stem cells which have reduced their ability to divide asymmetrically and hence divide symmetrically, generating increasing number of cancer stem cells, fostering tumor growth. We have previously demonstrated that the architectural transcription factor HMGA1 is highly expressed in brain tumor stem cells (BTSCs) and that its silencing increases stem cell quiescence, reduces self-renewal and sphere-forming efficiency in serial passages, suggesting a shift from symmetric to asymmetric division. Since NUMB expression is fundamental for the fulfillment of asymmetric division in stem cells, and is lost or reduced in many tumors, including GBM, we have investigated the ability of HMGA1 to regulate NUMB expression. Here, we show that HMGA1 negatively regulates NUMB expression at transcriptional level, by binding its promoter and counteracting c/EBP-β and at posttranscriptional level, by regulating the expression of MSI1 and of miR-146a. Finally, we report that HMGA1 knockdown-induced NUMB upregulation leads to the downregulation of the NOTCH1 pathway. Therefore, the data reported here indicate that HMGA1 negatively regulates NUMB expression in BTSCs, further supporting HMGA1 targeting as innovative and effective anti-cancer therapy.
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http://dx.doi.org/10.1080/15384101.2019.1618541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592240PMC
July 2019

Overexpression of Figures as a Potential Prognostic Factor in Endometrioid Endometrial Carcinoma (EEC).

Genes (Basel) 2019 05 15;10(5). Epub 2019 May 15.

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer-INCA, Rua André Cavalcanti, 37 - Centro, Rio de Janeiro, RJ 20231-050, Brazil.

Endometrioid endometrial carcinomas (EEC) are the most common malignant gynecologic tumors. Despite the increase in EEC molecular knowledge, the identification of new biomarkers involved in disease's development and/or progression would represent an improvement in its course. High-mobility group A protein (HMGA) family members are frequently overexpressed in a wide range of malignancies, correlating with a poor prognosis. Thus, the aim of this study was to analyze HMGA1 and HMGA2 expression pattern and their potential role as EEC biomarkers. HMGA1 and HMGA2 expression was initially evaluated in a series of 46 EEC tumors (stages IA to IV), and the findings were then validated in The Cancer Genome Atlas (TCGA) EEC cohort, comprising 381 EEC tumors (stages IA to IV). Our results reveal that HMGA1 and HMGA2 mRNA and protein are overexpressed in ECC, but only expression is associated with increased histological grade and tumor size. Moreover, but not overexpression was identified as a negative prognostic factor to EEC patients. Finally, a positive correlation between expression of pseudogenes- and -and HMGA1 itself was detected, suggesting HMGA1 pseudogenes may play a role in HMGA1 expression regulation in EEC. Thus, these results indicate that overexpression possesses a potential role as a prognostic biomarker for EEC.
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http://dx.doi.org/10.3390/genes10050372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562754PMC
May 2019

New Anti-Cancer Strategies in Testicular Germ Cell Tumors.

Recent Pat Anticancer Drug Discov 2019 ;14(1):53-59

Institute of Endocrinology and Experimental Oncology of the CNR c / o Department of Molecular Medicine and Medical Biotechnology, School of Medicine and Surgery of Naples, University of Naples 'Federico II', Naples, Italy.

Background: The most common solid malignancy of young men aged 20 to 34 years is testicular germ cell tumor. In addition, the incidence of these tumors has significantly increased throughout the last years. Testicular germ cell tumors are classified into seminoma and nonseminoma germ cell tumors, which take in yolk sac tumor, embryonal cell carcinoma, choriocarcinoma, and teratoma. There are noteworthy differences about therapy and prognosis of seminomas and nonseminoma germ cell tumors, even though both share characteristics of the primordial germ cells.

Objectives: The study is focused on different molecular mechanisms strongly involved in testicular germ cell line tumors underlying new strategies to treat this human neoplasia.

Methods: Bibliographic data from peer-reviewed research, patent and clinical trial literature, and around eighty papers and patents have been included in this review.

Results: Our study reveals that several biomarkers are usefully utilized to discriminate among different histotypes. Moreover, we found new patents regarding testicular germ cell tumor treatments such as the expression of claudin 6, monoclonal antibody (Brentuximab Vedotin), immune checkpoint blockade (ICB) with the FDA-approved drugs pembrolizumab and nivolumab or the oncolytic virus Pelareorep, the combination of selective inhibitors of Aurora kinase.

Conclusion: Finally, the pathogenesis of testicular germ cell tumor needs to be deeply understood so that it will improve data on stem cells, tumorigenesis and disease tumor management by more selective treatment.
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http://dx.doi.org/10.2174/1574892814666190111120023DOI Listing
December 2019

Characterization of inflammatory infiltrate of ulcerative dermatitis in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice.

Lab Anim 2019 Oct 6;53(5):447-458. Epub 2018 Dec 6.

Department of Veterinary Medicine and Animal Production, University of Naples Federico II, Italy.

Ulcerative dermatitis (UD) is an idiopathic, spontaneous and progressive disease typically affecting C57BL/6 aged mice with an unknown aetiopathogenesis. For this study, we evaluated 25 cases of UD in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice. Formalin-fixed, paraffin-embedded skin samples were submitted to morphological investigations. Immunohistochemical analysis was performed to characterize and quantify inflammatory cells using CD3, CD45/B220, CD4, CD8 and IL-17 antibodies. Mast cell-bound IgE was investigated by immunofluorescence, whereas serum and cryopreserved skin samples were collected for molecular analysis. Student's t-test (two-tailed) was performed to assess significant differences between the two groups. Affected skin showed extensive areas of ulceration and diffuse, severe and mixed inflammatory infiltrates. No relevant changes were observed in control mice. Immunohistochemical analysis showed a predominant CD3 + CD4 + leukocyte population with fewer CD45/B220 and IL-17 immunolabelled cells and mast cell-bound IgE. Increases in TNFα, IL-1β and Il-6 mRNA expression were observed in the skin of affected animals compared to controls. Serum TNFα and IL-6 did not vary between affected and control mice. Inflammatory infiltrates and cytokine expression were consistent with both Th2/IgE and Th17 differentiation, a typical pattern of a type I hypersensitivity reaction. Overall, our data suggest an allergic-based aetiopathogenesis of UD in C57BL/6NCrl-Tg(HMGA1P6)1Pg mice.
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http://dx.doi.org/10.1177/0023677218815718DOI Listing
October 2019

UBE2C Is a Transcriptional Target of the Cell Cycle Regulator FOXM1.

Genes (Basel) 2018 Mar 29;9(4). Epub 2018 Mar 29.

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer-INCA, Rua Andre Cavalcanti 37, Rio de Janeiro 20231-050, RJ, Brazil.

FOXM1 (forkhead box protein M1) is a transcription factor that participates in all stages of tumor development, mainly through the control of cell cycle and proliferation, regulating the expression of genes involved in G1/S and G2/M transition and M phase progression. The ubiquitin conjugating enzyme E2 (UBE2C) is a member of the anaphase promoting complex/cyclosome, promoting the degradation of several target proteins along cell cycle progression, during metaphase/anaphase transition. FOXM1 and UBE2C have been found overexpressed in a wide range of different solid tumors. Therefore, the aim of this study was to investigate whether is a transcriptional target of FOXM1, using esophageal squamous cell carcinoma (ESCC) as a model, in addition to several cancer-deposited data. Our results show that and expression present a positive correlation in normal tissues and in 25 distinct tumor types, including ESCC, where these genes are overexpressed. Moreover, FOXM1 binds to promoter region in ESCC cell line and transcriptionally activates it, leading to UBE2C upregulation. In conclusion, this study provides evidences that FOXM1 transcriptionally regulates expression in ESCC and their deregulation may be a general phenomenon in human neoplasias.
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http://dx.doi.org/10.3390/genes9040188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924530PMC
March 2018

HMGA2, but not HMGA1, is overexpressed in human larynx carcinomas.

Histopathology 2018 Jun 9;72(7):1102-1114. Epub 2018 Mar 9.

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer - INCA, Rio de Janeiro, Brazil.

Aims: Malignant tumours from the upper aerodigestive tract are grouped collectively in the class of head and neck squamous cell carcinoma (HNSCC). The head and neck tumours were responsible for more than 500 000 cancer cases in 2012, accounting for the sixth highest incidence rate and mortality worldwide among all tumour types. Laryngeal squamous cell carcinoma (LSCC) possesses the second highest incidence rate among all HNSCC. Despite significant advances in surgery and radiotherapy during the last few decades, no treatment has been shown to achieve a satisfactory therapeutic outcome and the mortality rate of LSCC is still high, with a 5-year survival rate of 64%. Therefore, further investigations are required to identify the pathogenesis of LSCC.

Methods And Results: In order to search for new LSCC biomarkers, we have analysed the expression of the HMGA family members, HMGA1 and HMGA2, by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. HMGA proteins are usually absent in the healthy adult tissues. In contrast, their constitutive expression is a feature of several neoplasias, being associated with a highly malignant phenotype and reduced survival. Here, we report HMGA2 overexpression in larynx carcinomas. Conversely, HMGA1 does not show any differences in its expression between normal and carcinoma tissues. Interestingly, HMGA2 overexpression appears associated with that of two HMGA1-pseudogenes, HMGA1P6 and HMGA1P7, acting as a sponge for HMGA1- and HMGA2-targeting microRNAs and involved in several human cancers.

Conclusions: Therefore, HMGA2 overexpression appears to be a strong feature of larynx carcinoma, supporting its detection as a valid tool for the diagnosis of these malignancies.
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http://dx.doi.org/10.1111/his.13456DOI Listing
June 2018

The HMGA1 Pseudogene 7 Induces miR-483 and miR-675 Upregulation by Activating Egr1 through a ceRNA Mechanism.

Genes (Basel) 2017 Nov 17;8(11). Epub 2017 Nov 17.

Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli "Federico II", via Pansini, 5, 80131 Naples, Italy.

Several studies have established that pseudogene mRNAs can work as competing endogenous RNAs and, when deregulated, play a key role in the onset of human neoplasias. Recently, we have isolated two pseudogenes, and . These pseudogenes have a critical role in cancer progression, acting as micro RNA (miRNA) sponges for and other cancer-related genes. pseudogenes were found overexpressed in several human carcinomas, and their expression levels positively correlate with an advanced cancer stage and a poor prognosis. In order to investigate the molecular alterations following pseudogene overexpression, we carried out miRNA sequencing analysis on overexpressing mouse embryonic fibroblasts. Intriguingly, the most upregulated miRNAs were miR-483 and miR-675 that have been described as key regulators in cancer progression. Here, we report that upregulates miR-483 and miR-675 through a competing endogenous RNA mechanism with , a transcriptional factor that positively regulates miR-483 and miR-675 expression.
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http://dx.doi.org/10.3390/genes8110330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704243PMC
November 2017

Overexpression of Chromosome 21 miRNAs May Affect Mitochondrial Function in the Hearts of Down Syndrome Fetuses.

Int J Genomics 2017 5;2017:8737649. Epub 2017 Sep 5.

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Dosage-dependent upregulation of most of chromosome 21 (Hsa21) genes has been demonstrated in heart tissues of fetuses with Down syndrome (DS). Also miRNAs might play important roles in the cardiac phenotype as they are highly expressed in the heart and regulate cardiac development. Five Hsa21 miRNAs have been well studied in the past: miR-99a-5p, miR-125b-2-5p, let-7c-5p, miR-155-5p, and miR-802-5p but few information is available about their expression in trisomic tissues. In this study, we evaluated the expression of these miRNAs in heart tissues from DS fetuses, showing that miR-99a-5p, miR-155-5p, and let-7c-5p were overexpressed in trisomic hearts. To investigate their role, predicted targets were obtained from different databases and cross-validated using the gene expression profiling dataset we previously generated for fetal hearts. Eighty-five targets of let-7c-5p, 33 of miR-155-5p, and 10 of miR-99a-5p were expressed in fetal heart and downregulated in trisomic hearts. As nuclear encoded mitochondrial genes were found downregulated in trisomic hearts and mitochondrial dysfunction is a hallmark of DS phenotypes, we put special attention to let-7c-5p and miR-155-5p targets downregulated in DS fetal hearts and involved in mitochondrial function. The let-7c-5p predicted target was identified as a possible candidate for both mitochondrial and cardiac anomalies.
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http://dx.doi.org/10.1155/2017/8737649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605795PMC
September 2017

Role of Dicer1 in thyroid cell proliferation and differentiation.

Cell Cycle 2017 9;16(23):2282-2289. Epub 2017 Nov 9.

a Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" , Naples , Italy.

DICER1 plays a central role in the biogenesis of microRNAs and it is important for normal development. Altered microRNA expression and DICER1 dysregulation have been described in several types of tumors, including thyroid carcinomas. Recently, our group identified a new somatic mutation (c.5438A>G; E1813G) within DICER1 gene of an unknown function. Herein, we show that DICER1 is overexpressed, at mRNA level, in a significant-relative number of papillary (70%) and anaplastic (42%) thyroid carcinoma samples, whereas is drastically downregulated in all the analyzed human thyroid carcinoma cell lines (TPC-1, BCPAP, FRO and 8505c) in comparison with normal thyroid tissue samples. Conversely, DICER1 is downregulated, at protein level, in PTC in comparison with normal thyroid tissues. Our data also reveals that DICER1 overexpression positively regulates thyroid cell proliferation, whereas its silencing impairs thyroid cell differentiation. The expression of DICER1 gene mutation (c.5438A>G; E1813G) negatively affects the microRNA machinery and cell proliferation as well as upregulates DICER1 protein levels of thyroid cells but has no impact on thyroid differentiation. In conclusion, DICER1 protein is downregulated in papillary thyroid carcinomas and affects thyroid proliferation and differentiation, while DICER1 gene mutation (c.5438A>G; E1813G) compromises the DICER1 wild-type-mediated microRNA processing and cell proliferation.
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http://dx.doi.org/10.1080/15384101.2017.1380127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788491PMC
July 2019

miR-155 is positively regulated by CBX7 in mouse embryonic fibroblasts and colon carcinomas, and targets the KRAS oncogene.

BMC Cancer 2017 03 4;17(1):170. Epub 2017 Mar 4.

Istituto di Endocrinologia ed Oncologia Sperimentale "G. Salvatore" - CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Naples, Italy.

Background: Loss of CBX7 expression has been described in several malignant neoplasias, including human colon and thyroid carcinomas proposing CBX7 as a tumor suppressor gene with a key role in cancer progression. This role is supported from the development of benign and malignant neoplasias in Cbx7 null mice. The aim of our work has been to investigate the mechanisms underlying the CBX7 oncosuppressor activity by analyzing the microRNAs (miRNAs) regulated by CBX7.

Methods: The miRNA expression profiles of the mouse embryonic fibroblasts (MEFs) null for Cbx7 and the wild-type counterpart were analyzed by the miRNACHIP microarray and then validated by qRT-PCR. To asses KRAS as target of miR-155 we evaluated the protein levels after transfection of the synthetic miR-155. Human colon carcinoma samples have been investigated for the expression of CBX7 and miR-155.

Results: Twenty miRNAs were found upregulated and nine, including miR-155, downregulated in cbx7-null MEFS in comparison with the wild-type ones. Then, we focused on miR-155 since several studies have shown its deregulated expression in several human malignancies and, moreover, was the most downregulated miRNA. Subsequently, we searched for miR-155 target genes demonstrating that KRAS protein levels are directly modulated by miR-155. A direct significant correlation (r = 0.6779) between CBX7 and miR-155 expression levels was found in a set of human colon carcinoma tissue samples.

Conclusion: miR-155 is positively regulated by CBX7 in MEFs and colon carcinomas, and has KRAS as one of the target genes likely accounting for the anti-apoptotic activity ascribed to miR-155 in some tissue contexts.
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http://dx.doi.org/10.1186/s12885-017-3158-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336640PMC
March 2017

HMGA1P7-pseudogene regulates H19 and Igf2 expression by a competitive endogenous RNA mechanism.

Sci Rep 2016 11 22;6:37622. Epub 2016 Nov 22.

Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli "Federico II", via Pansini 5, 80131 Naples, Italy.

Recent studies have revealed that pseudogene transcripts can function as competing endogenous RNAs, and thereby can also contribute to cancer when dysregulated. We have recently identified two pseudogenes, HMGA1P6 and HMGA1P7 for the HMGA1 gene whose overexpression has a critical role in cancer progression. These pseudogenes work as competitive endogenous RNA decoys for HMGA1 and other cancer related genes suggesting their role in carcinogenesis. Looking for new HMGA1 pseudogene ceRNAs, we performed RNA sequencing technology on mouse embryonic fibroblasts deriving from transgenic mice overexpressing HMGA1P7. Here, we report that HMGA1P7 mRNA sustains the H19 and Igf2 overexpression by acting as miRNA decoy. Lastly, the expression of HMGA1P7 was significantly correlated with H19 and IGF2 levels in human breast cancer thereby suggesting a role for HMGA1P7 deregulation in this neoplasia.
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http://dx.doi.org/10.1038/srep37622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118720PMC
November 2016

UBE2C is overexpressed in ESCC tissues and its abrogation attenuates the malignant phenotype of ESCC cell lines.

Oncotarget 2016 10;7(40):65876-65887

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer - INCA, Rio de Janeiro, Brazil.

The esophageal squamous cell carcinoma (ESCC) is widely known as a highly lethal and poor understood cancer, then requiring the search for novel molecular markers to improve its management and patients survival. Recently, ubiquitin-conjugating enzyme E2C (UBE2C) has been figuring as a prominent tumor biomarker candidate, once it has been recognized as a key player in cell cycle progression. In this way, the aim of this study was to evaluate the expression profile of UBE2C gene and protein in ESCC samples, as well as its diagnostic and prognostic marker potential, and its contribution to ESSC genesis and/or progression by performing in vitro functional assays. The analysis of UBE2C gene expression in 52 paired ESCC samples (tumor and respective histologically normal surrounding tissue), by qRT-PCR, revealed that this gene is overexpressed in 73% of ESCC samples. Subsequently, immunohistochemical analysis confirmed that UBE2C protein expression was upregulated in all ESCC cases, but absent in the histologically normal tumor surrounding tissues. Moreover, we showed that UBE2C mRNA expression was able to accurately discriminate ESCC tissue from both healthy esophageal and histologically normal tumor surrounding tissues, pointing out its role as a diagnostic marker for this cancer. Finally, we report that UBE2C affects proliferation rates and cell cycle profile of ESCC cell lines, by directly interfering with cyclin B1 protein levels, suggesting its involvement in crucial steps of ESCC carcinogenesis.
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http://dx.doi.org/10.18632/oncotarget.11674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323199PMC
October 2016

HMGA2 overexpression plays a critical role in the progression of esophageal squamous carcinoma.

Oncotarget 2016 May;7(18):25872-84

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer - INCA, Rio de Janeiro, RJ, Brazil.

Esophageal Squamous Cell Carcinoma (ESCC) is the most common esophageal tumor worldwide. However, there is still a lack of deeper knowledge about biological alterations involved in ESCC development. High Mobility Group A (HMGA) protein family has been related with poor outcome and malignant cell transformation in several tumor types. In this way, the aim of this study was to analyze the expression of HMGA1 and HMGA2 expression in ESCC and their role in crucial cellular features. We evaluated HMGA1 and HMGA2 mRNA expression in 52 paired ESCC and normal surrounding tissue samples by qRT-PCR. Here, we show that HMGA2, but not HMGA1, is overexpressed in ESCC samples. This result was further confirmed by the immunohistochemical analysis. Indeed, accordingly to mRNA expression data, HMGA2, but not HMGA1, was overexpressed in approximately 90% of ESCC samples, while it was barely expressed in the respective control. Conversely, HMGA1, but not HMGA2, was overexpressed in esophageal adenocarcinoma samples. Interestingly, HMGA2 abrogation attenuated the malignant phenotype of two ESCC cell lines, suggesting that HMGA2 overexpression is involved in ESCC progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5041951PMC
http://dx.doi.org/10.18632/oncotarget.8288DOI Listing
May 2016

HMGA1-pseudogenes and cancer.

Oncotarget 2016 May;7(19):28724-35

Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli "Federico II", Naples, Italy.

Pseudogenes are DNA sequences with high homology to the corresponding functional gene, but, because of the accumulation of various mutations, they have lost their initial functions to code for proteins. Consequently, pseudogenes have been considered until few years ago dysfunctional relatives of the corresponding ancestral genes, and then useless in the course of genome evolution. However, several studies have recently established that pseudogenes are owners of key biological functions. Indeed, some pseudogenes control the expression of functional genes by competitively binding to the miRNAs, some of them generate small interference RNAs to negatively modulate the expression of functional genes, and some of them even encode functional mutated proteins. Here, we concentrate our attention on the pseudogenes of the HMGA1 gene, that codes for the HMGA1a and HMGA1b proteins having a critical role in development and cancer progression. In this review, we analyze the family of HMGA1 pseudogenes through three aspects: classification, characterization, and their possible function and involvement in cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053758PMC
http://dx.doi.org/10.18632/oncotarget.7427DOI Listing
May 2016

miR-130b-3p Upregulation Contributes to the Development of Thyroid Adenomas Targeting CCDC6 Gene.

Eur Thyroid J 2015 Dec 21;4(4):213-21. Epub 2015 Nov 21.

Istituto di Endocrinologia ed Oncologia Sperimentale-CNR, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Scuola di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli 'Federico II', Naples, Italy; Instituto Nacional de Cancer (INCA), Rio de Janeiro, Brazil.

We have previously studied the function of microRNAs (miRNAs) in thyroid cells using the differentiated rat thyroid PC Cl 3 cells that need thyrotropin (TSH) for their growth. The miRNA expression profile examination allowed the detection of a set of miRNAs downregulated and upregulated by TSH. Here, we first demonstrated that upregulation of miR-130b-3p occurs through a protein kinase A-cAMP-responsive element binding protein (CREB)-dependent mechanism. Then, we analyzed its expression in human thyroid follicular adenomas, where a constitutive CREB activation is frequently present. miR-130b-3p results in upregulation with a high fold-change in most thyroid follicular adenomas. Then, we identified CCDC6, coding for a protein that interacts with CREB1 leading to the transcriptional repression of CREB1 target genes, as a target of this miRNA. The targeting of CCDC6 by miR-130b-3p likely accounts for the mechanism by which its upregulation contributes to the development of thyroid adenomas increasing CREB1 activity.
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http://dx.doi.org/10.1159/000441355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716415PMC
December 2015
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